The majority of acute coronary syndromes occur as a result of plaque rupture at sites with noncritical luminal narrowing. The Integrated Biomarker and Imaging Study (IBIS) integrated several imaging modalities in conjunction with multiple biomarkers to evaluate patients with subclinical coronary atherosclerosis. Multislice computed tomography coronary angiography showed good accuracy to detect nonobstructive coronary plaque. In contrast to conventional imaging that reveals static luminal and plaque dimensions on standard medical therapy, intravascular ultrasound-based palpography detected changes in biomechanical plaque characteristics over a 6-month period. The results of this study might prove helpful for future studies aiming to identify the patient at risk for future acute coronary events.

Abstract

Objectives Our purpose was to assess noninvasive imaging in detection of subclinical atherosclerosis and to examine novel invasive modalities to describe prevalence and temporal changes in putative characteristics of “high-risk” plaques.

Methods Conventional (quantitative angiography and intravascular ultrasound [IVUS]) and novel imaging (IVUS-based palpography and gray scale echogenicity) were performed at baseline and 6 months later in 67 patients with diverse clinical presentations. Different imaging techniques were compared within a common segment defined by multislice computed tomography (MSCT).

Results Compared with IVUS, the sensitivity, specificity, and positive and negative predictive value of MSCT for detecting significant plaque was 86%, 69%, 90%, and 61%, respectively. In coronary arteries with <50% stenosis, there were no temporal changes in luminal and plaque dimensions measured by quantitative coronary angiography or IVUS; however, a significant reduction in abnormal strain pattern was detected on palpography (density high strain spots/cm: 1.6 ± 1.5 vs. 1.2 ± 1.4, p = 0.0123. These changes were mainly related to significant changes in patients who presented with ST-segment elevation myocardial infarction. The assessment of plaque echogenicity showed no temporal changes. There were no correlations between circulating biomarkers and quantifiable imaging parameters.

Atherosclerosis is a systemic disease in which the clinical sequelae only weakly correlate with its extent or severity. Furthermore, sudden death or acute coronary syndromes are frequently the first manifestation of previously subclinical atherosclerosis, and the majority of such events (i.e., 60% to 70%) occur as a result of plaque rupture at sites with noncritical luminal narrowing (1–5). Pathologic studies have correlated specific coronary plaque characteristics with fatal ischemic events, but conventional imaging techniques, such as quantitative angiography and quantitative intravascular ultrasound (IVUS), cannot reliably identify high-risk, rupture-prone, plaques prospectively (6). Thus, development of novel coronary imaging modalities to detect structural and compositional plaque characteristics has been the subject of intensive preclinical and clinical research (7,8). In parallel with the advances in novel invasive imaging, noninvasive multislice computed tomographic angiography (MSCTA) has matured to the extent that it can reliably identify flow-limiting coronary lesions in relatively unselected patients.

The aim of this study was four-fold: 1) to determine the potential of MSCTA in the detection of subclinical, non-flow limiting coronary atherosclerosis; 2) to assess the prevalence of high-risk characteristics in such plaques with two novel IVUS-based imaging modalities (palpography and echogenicity plaque characterization); 3) to assess temporal changes in IVUS-based plaque characteristics of high-risk lesions; and 4) we attempted to relate changes in imaging parameters to changes in systemic biomarker levels.

Methods

Study design and patient selection

This was a prospective, observational, single-center pilot study. The study design has been described in detail elsewhere (9). Briefly, patients with stable angina, unstable angina, non–ST-segment elevation, or ST-segment elevation myocardial infarction (STEMI), referred for percutaneous coronary intervention (PCI), were eligible for inclusion. Major clinical exclusion criteria included significant renal dysfunction (creatinine >2 mg/dl), prior coronary intervention in the region of interest (ROI), life expectancy <1 year, or factors that made follow-up difficult. Major imaging-related exclusion criteria included coronary anatomy that precluded safe IVUS examination of a suitable ROI or criteria that precluded acquisition of diagnostic noninvasive angiographic images (irregular heart rhythm or inability to hold breath for 20 s). Between March 2003 and November 2003, 90 consecutive patients were enrolled, and follow-up was completed in summer 2004. The study vessel was preferably a non-intervened artery. At the discretion of the operator, a second artery could be studied. The ROI was defined on the basis of MSCTA, using landmarks, such as branches or the vessel origin. At six months follow-up, patients underwent repeat invasive imaging. The medical ethics committee of the Erasmus Medical Center Rotterdam approved the study protocol, and all patients provided written informed consent.

Quantitative coronary angiography and IVUS

Quantitative angiographic analyses were performed by a core laboratory (Cardialysis, Rotterdam, the Netherlands) with the use of edge-detection techniques (CAAS II, Pie Medical, Maastricht, the Netherlands). Mean and minimum luminal diameters and diameter stenosis were measured in at least two, preferentially orthogonal, projections and averaged.

The IVUS was performed with commercially available catheters (30 MHz, Ultracross, or 40 MHz, Atlantis SR Pro, Boston Scientific, Santa Clara, California) using standard procedures with an automated pullback device (0.5 mm/s) (10). Data were stored on videotape, transformed into the Digital Imaging and Communication in Medicine (DICOM) image standard, and archived. Quantitative analysis was performed by the core laboratory with validated software (Curad, version 3.1, Wijk bij Duurstede, the Netherlands) and retrospective image-based gating (11). The borders of the external elastic membrane (EEM) and of the lumen were traced. The enclosed area was defined as the coronary plaque plus media area (subsequently referred to as plaque area). Significant plaque was defined as a plaque that occupied 50% or more of the cross-sectional vessel area circumscribed by the EEM. Other IVUS measurements included length of the ROI, lumen volume, and vessel volume. Plaque volume (PV) was calculated as vessel volume minus lumen volume. The interobserver variability was determined by re-analyzing the baseline and follow-up IVUS recordings of 16 patients by a different core lab analyst. Sixteen patients (32 recordings) were randomly selected among recordings that fulfilled the following two criteria: 1) ROI >30 mm long, and 2) both pullbacks were performed with the same type of IVUS catheter (30 MHz catheter).

Novel IVUS-based plaque imaging: echogenicity

We used a computer-aided, gray-scale value analysis program for plaque characterization (12). On the basis of the mean gray level (brightness) of the adventitia, plaque was classified as brighter (hyperechogenic) or less bright (hypoechogenic) than the adventitia. Calcified plaque was defined as plaque brighter than the adventitia with associated acoustic shadowing. The variables measured in the previously defined ROI included hypoechogenic PV and hyperechogenic PV (mm3) and relative plaque echogenicity, calculated as (hypoechogenic PV/sum of hypoechogenic and hyperechogenic PV) × 100. For the comparison with MSCT, plaque within the ROI was considered calcified if it contained calcium in at least two consecutive cross-sections corresponding to an IVUS segment with a length of at least 0.5 mm.

Novel IVUS-based plaque imaging: palpography

Palpography is an IVUS-based technique that assesses the local mechanical properties of the coronary plaque. The technique measures the relative displacements of backscattered radiofrequency signals, recorded during IVUS acquisition, at two different blood pressure levels to detect differences in deformability or strain of various plaque components. As such, lipid-rich plaques will deform more and thus show a higher strain value compared with calcified or fibrous plaques (13). Palpography data were acquired during an IVUS pullback (1 mm/s) with a commercially available catheter (20 MHz Jovus Avanar, Volcano, Rancho Cordova, California). With previously described and validated methodology, plaque strain values were assigned a ROtterdam Classification (ROC) score ranging from 1 to 4 (ROC 1: 0% to 0.6%; ROC 2: 0.6% to <0.9%; ROC 3: 0.9% to <1.2%; ROC 4: >1.2%) (13–16). The parameters measured included the number of ROC 3 or 4 spots in the ROI and the density of ROC 3/4 spots, defined as the total number of ROC 3 and 4 scores that were counted in all cross sections that were acquired at 1-mm intervals in the whole ROI. This number was divided by the length of the ROI and multiplied by 10 to normalize to the pullback length.

MSCTA

All scans were performed on a 16-row detector scanner (Sensation 16, Straton, Siemens, Forchheim, Germany). The scan protocol and image reconstruction parameters were recently published (17). The dataset with least motion artifacts was loaded on an off-line workstation (Leonardo, Siemens) and the ROI identified on multiplanar reconstructions, on the basis of anatomic landmarks. Datasets were loaded on a semi-automated vessel-tracking software program and a central lumen line created throughout the ROI. Ten through 30 cross sections were reconstructed orthogonal to the center of the lumen and analyzed independently by two observers. Disagreements were resolved by consensus. Plaque was defined as an abnormal mass within the artery wall, clearly distinguishable from epicardial fat and the coronary lumen. On the basis of manually measured maximal thickness, plaques were classified as small (<1 mm), medium (1 to 2 mm), or large (>2 mm). Calcification was defined by the presence of high-density components (>130 Hounsfield units).

Definition of events and follow-up for major adverse cardiac events

The occurrence of major adverse cardiovascular events was assessed after the procedure, at discharge, and at three and six months, as were the individual components: death, myocardial infarction (MI), revascularization by PCI or coronary artery bypass graft surgery, hospital stay for ischemia and/or anginal symptoms, and stroke. The diagnosis of MI was consistent with the American College of Cardiology/European Society of Cardiology definition (19).

Statistical analysis

Discrete variables are presented as counts and percentages. Continuous variables are presented as means ± SD, unless otherwise indicated. Comparisons between quantitative outcomes were performed with use of scatter plots and linear regression analysis (regression coefficient). When appropriate, biomarker analyses were performed after natural logarithmic transformation. Correlations between imaging end points and circulating biomarkers were assessed, and univariate Pearson correlation coefficients were calculated. Comparisons among patient subgroups, grouped by clinical presentation, with findings on palpography and on echogenicity, were performed at both vessel and patient level. In the latter case, the imaging findings from two ROIs in the same patient were averaged. Differences in means among groups were analyzed by a two-sample ttest. A value p < 0.05 (two-sided) was indicative of statistical significance. No formal hypotheses were tested in this exploratory study; therefore p values are given as such, without any correction for multiplicity of testing. Statistical analyses were performed with the Statistical Analysis System software version 8.2 (SAS Institute, Cary, North Carolina).

Results

Patient population

A flow diagram detailing the number of patients undergoing multimodality coronary imaging is presented in Figure 1.Sixty-seven patients underwent serial invasive imaging of non-culprit segments of coronary artery at baseline and 196 ± 19 days later. Nine patients had one or both IVUS recordings that were not analyzable, owing to artifact or use of an incorrect scale. An additional three patients could not be analyzed for IVUS echogenicity, owing to extensive calcification overshadowing a large part of the adventitia, which is used as a reference for the interpretation of gray-scale values of surrounding tissue. Reasons for inaccurate palpogram readings (n = 18) were related to extensive catheter motion during data acquisition. Baseline characteristics of patients who completed the study are shown in Table 1.They were comparable to those of the entire cohort of 84 patients enrolled at baseline (not shown). Almost all patients (99%) received treatment with a statin within the six-month study period, mainly as a result of starting treatment in the group who presented initially with STEMI (treatment started in 13 of 14 STEMI patients). Mean total cholesterol, LDL-C, HDL-C, and triglyceride values for patients who completed the study are presented in Table 2.

MSCTA versus IVUS at baseline

The MSCTA and IVUS were compared, at baseline, in 61 patients (67 vessels). The sensitivity and specificity of MSCTA to detect significant plaque identified on IVUS (>50% EEM area obstruction or the presence of calcification on two consecutive slices) was calculated for the entire ROI and for 5-mm sub-segments (Table 3).The sensitivity, specificity, and positive and negative predictive values of MSCTA for detection of any significant plaque was 86%, 69%, 90%, and 61%, respectively. The sensitivity of MSCTA to detect plaque was 60% (30 of 50) for small (<1 mm), 76% (80 of 105) for medium (1 to 2 mm), and 79% (26 of 33) for large (>2 mm) plaques.

Conventional imaging: quantitative coronary angiography and IVUS

There were no statistically significant changes in the angiographic variables measured in the ROI (Table 4).Likewise, IVUS-derived measurements remained unchanged in matched segments (Table 5).Figure 2illustrates the spread of the individual data points for PV. When patients were grouped according to initial diagnosis (i.e., STEMI, unstable angina, stable angina), there were no significant changes in either angiographic or IVUS measurements between baseline and follow-up (data not shown).

Novel IVUS-based imaging

Temporal changes in plaque characteristics on the basis of IVUS-based palpography and echogenicity are shown in Tables 5 and 6.⇓At baseline, the predominant plaque component was hypoechogenic tissue (91.6% of PV). There was no significant change in the absolute volume of hypoechogenic or hyperechogenic plaque over the course of the study. On palpography, both the absolute number of high-strain spots (grade 3/4) in the ROI (p = 0.009) and their density per cm (p = 0.012) decreased significantly between baseline and follow-up. This decrease in the overall population was largely driven by changes in the subgroup of patients with STEMI; this group had both the highest number of high-strain spots at baseline and the most marked relative decrease during follow-up, compared with patients with other clinical presentations. At 6-month follow-up, the density of high-strain spots (1.2 ± 1.4/cm) was comparable among clinical subgroups. Representative imaging findings are presented in Figure 3.

Example of multimodality coronary imaging of the proximal left anterior descending coronary artery. (A, B)Region of interest (ROI) is defined by the ostium of the left anterior descending and a large septal branch, as marked by white lineson the conventional angiogram (A)and arrowheadson multislice computed tomography maximum intensity projection reconstruction (B). (C)Gated longitudinal intravascular ultrasound (IVUS) reconstruction. The vertical linesmark the boundaries of the ROI. The red lineindicates the lumen-intima interface and the green linethe external border of the plaque plus echolucent media. (D, E)Representative color-coded cross-sectional palpograms that are superimposed on the IVUS image. Strain values are color-coded from 0% (blue)to 2% (yellow), as shown on the vertical scale. (D)Shows non-deformable eccentric plaque with calcification and acoustic shadowing. The blue linearound the lumen indicates a non-deformable plaque with 0% strain. In the regions without plaque, the gray colorindicates that no strain value can be measured. (E)Shows eccentric partly calcified plaque with a high strain (yellow)spot on one shoulder of the plaque (nine o’clock). On the other shoulder (four o’clock) the blue color(0% strain) indicates that the plaque is not deformable in this region. (F, G)Representative color-coded echogenicity cross sections. Hypoechogenic tissue is represented in redand hyperechogenic tissue in green. (F)Shows a cross section with a relatively large hyperechogenic area. The white spotsvisible most likely represent thick fibrous tissue and not calcification, because there was no acoustic shadowing on the corresponding IVUS images (not shown). (G)Shows a cross section, which predominantly contains hypoechogenic tissue. (H)Multislice computed tomography reconstruction and (inset)a cross section in an area with calcified plaque (arrows).

Correlation of biomarkers with imaging techniques

Not surprisingly, several inflammatory mediators (C-reactive protein, interleukin-6, lipoprotein-associated phospholipase A2) and a marker of hemodynamic stress (NT-proBNP) decreased over time, particularly in patients presenting with acute coronary syndromes. There were no significant correlations noted between circulating biomarkers and imaging parameters (data not shown). Among lipid parameters (total cholesterol, LDL-C, HDL-C, and triglycerides), a correlation with the change in IVUS-derived plaque area was only noted for the change in HDL-C (Pearson correlation coefficient −0.37, p < 0.05, data not shown).

Adverse events

One patient died two weeks after inclusion, because of a second MI. All imaging procedures were performed without complications.

Discussion

The major findings of the study were four-fold. First, with IVUS as a gold standard, noninvasive MCSTA can identify atherosclerotic plaque, in vessels with only minimal angiographic disease, with high sensitivity and moderate specificity. Second, further investigation of such plaque with novel IVUS-based imaging techniques (palpography and echogenicity) showed that features potentially indicative of vulnerable plaques are both widespread and highly prevalent. Third, although conventional imaging with quantitative coronary angiography and IVUS demonstrates no significant changes in lumen or plaque dimensions, the biomechanical properties of the plaques, assessed by palpography, showed significant changes over a relatively short period. Finally, circulating levels of measured biomarkers showed no significant correlations with focal imaging end points identified by conventional and novel imaging modalities.

Subclinical atherosclerosis: role of noninvasive imaging

The development of noninvasive angiography with MSCTA can be used to reliably identify significant epicardial coronary atherosclerosis (20). Recent studies have shown its potential for detecting non-obstructive coronary plaques in highly selected patients (21,22). Our results extend these findings by showing that non-obstructive coronary plaque can be detected, in an arbitrarily selected ROI, with moderately high sensitivity and specificity in a broader patient population; however, when examined in more detail, with novel invasive techniques, we found that putative “high-risk” characteristics (i.e., hypoechogenic plaques with a high-strain pattern) were very common. This observation provides additional arguments to support recommendations discouraging the indiscriminate use of noninvasive coronary imaging to detect subclinical atherosclerosis at the present time (23).

Subclinical atherosclerosis: insights from novel invasive techniques

We have previously validated the potential of palpography to identify thin-capped fibroatheromas in vitro (13,14,24,25). Subsequently, we showed that the number of high-strain spots in culprit epicardial vessels was correlated with clinical presentation (16). The present study extends these findings by demonstrating that, within arbitrarily selected segments of non-culprit vessels, high-strain areas were quite common, despite only mild angiographic disease. The most marked changes occurred in patients with an acute MI, most of who were statin-naïve (93%) at the time of the initial presentation. Although acute MI patients had a higher extent of high strain spots, all subgroups were comparable six months later, regardless of the initial presentation. Interestingly, the persistence of abnormal strain patterns might reflect the inadequacy of standard medical care. This hypothesis would be consistent with recent data that indicate the need for intensive intervention for LDL-C (<70 mg/dl) and inflammation (C-reactive protein <2 mg/l) to achieve the best clinical outcomes in the course of therapy with statins in post-ACS patients (26,27).

Prior studies suggest that gray-scale echogenicity is related to the histological components of carotid and coronary plaques (28–30). Although carotid plaque echogenicity can be assessed noninvasively, assessment of coronary plaque echogenicity requires invasive techniques and has been restricted to research settings. In the present study, we used a quantitative computer-assisted index of echogenicity, on the basis of gray-scale values of adventitia, and demonstrated that hypoechogenic tissue was the predominant plaque component. We found no significant change in absolute hypoechogenic or hyperechogenic PV over the average six months. Our findings differ from the observations of Schartl et al. (31), who found a small but significant increase in the hyperechogenic plaque component; however, their study had a longer follow-up period and patients had intensive, carefully monitored, statin therapy. A recent study conducted at our institution suggested that the changes in plaque echogenicity require a much longer period to occur (more than two years) (32). Accordingly, the high preponderance of hypoechogenic plaque (>90% of the PV) coupled with the lack of significant change during the short-term follow-up suggests that plaque echogenicity lacks the discrimination necessary either for risk stratification or as a surrogate measure of plaque composition on serial studies.

Study limitations

This observational study has limitations. First, our patient population was intentionally heterogeneous, and the study was underpowered to correlate compositional imaging end points with clinical outcomes. Although follow-up was incomplete (67 of 84, 80%), it compares favorably with recent serial IVUS studies (33,34). Moreover, baseline characteristics of the 67 patients with completed follow-up were the same as in the overall study population. Second, the present study did not demonstrate changes in plaque size. By contrast, recently published studies demonstrated regression of coronary atherosclerosis in patients with acute coronary syndromes treated with aggressive statin regimen (34). In contrast, in those with stable coronary artery disease maximal dose of atorvastatin given for 18 months only halted plaque growth (33). Potential explanation for these disparate results may be due to different duration of follow-up (6 vs. 18 months), underlying index event (stable vs. acute coronary syndrome), or suboptimal intensity of statin treatment noted in many IBIS patients that reflects slow adoption of current guidelines into clinical practice settings. With these caveats, however, data from recent trials, such as Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT), indicate that intensive treatment with statins affects plaque size and event rates, respectively (33,35). Third, although our results underscore the heterogeneity of coronary atheroma, much larger studies are needed to ultimately define the role of novel plaque imaging techniques in clinical practice. Fourth, our attempt to relate circulating biomarkers to coronary plaque imaging in an arbitrarily selected ROI can only be regarded as exploratory. We did not further discuss this possible interaction because the correlations we found were weak. Fifth, the suboptimal spatial and temporal resolution of the 16-slice MSCT scanner precludes accurate assessment of coronary artery segments <2 mm. Although the ROI as selected by MSCT was chosen randomly, distal coronary segments are inevitably underrepresented. The same argument holds true, however, for IVUS examination of the coronary tree, where for safety reasons only the larger coronary segments are targeted for interrogation.

Conclusions

Mild angiographic disease is associated with large atherosclerotic plaques identified with noninvasive MSCTA. This study also confirms that conventional invasive imaging modalities frequently reveal static luminal and plaque dimensions, whereas novel IVUS-based plaque palpography can detect significant alterations in coronary plaque characteristics over a relatively short time interval. Our results highlight the dynamic changes in the strain of coronary plaques that are remote from the culprit lesions, particularly in patients with MI. Whether the persistence of a high-strain pattern is a harbinger of cardiovascular events remains to be determined in much larger future studies. The novel imaging modalities used in this study provide insights into plaque biology, whereas temporal changes detected with these modalities might eventually serve as intermediate end points in interventional trials.

Footnotes

This study was supported by a research grant from GlaxoSmithKline, Philadelphia, Pennsylvania.

(2001) American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol37:1478–1492.

(2000) Myocardial infarction redefined–a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol36:959–969.

(2000) American College of Cardiology/American Heart Association Expert Consensus document on electron-beam computed tomography for the diagnosis and prognosis of coronary artery disease. Circulation102:126–140.

(2004) Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH study. Circulation110:1061–1068.

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